Inhibition of Janus kinases by tyrosine phosphorylation inhibitor, Tyrphostin AG-490
Inhibition of Janus kinases by tyrosine phosphorylation inhibitor, Tyrphostin AG-490
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DOI：
10.1080/07391102.2015.1050696
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发表时间：
2015-11-02
影响因子：
4.4
通讯作者：
Shafique, Shagufta
中科院分区：
文献类型：
--
作者：
Rashid, Sajid;Bibi, Nousheen;Shafique, Shagufta
Janus激酶（JAK）属于酪氨酸激酶的重要家族，涉及多种癌症类型的病理生理学，并且充当显著的治疗靶标。迄今为止，已经鉴定了许多有效的ATP竞争性（PTK结构域）或非ATP竞争性JAK抑制剂。其中Tyrphostin AG-490（2-氰基-3-（3，4-二羟基苯基）-N-（苯甲基）-2-丙烯酰胺）是一种众所周知的ATP竞争性抑制剂。然而，其作用模式，相互作用的残基的细节，并在JAK特异性结合位点诱导的构象变化仍然难以捉摸。在这里，通过比较结构分析，分子对接和分子动力学模拟试验，我们探索了AG-490对JAK 1，JAK 2和JAK 3的比较结合模式。我们的研究结果需要值得注意的观察AG-490的结合亲和力，说明独特的氨基酸残基躺在保守的ATP结合结构域的JAK家族成员。通过随后对其结构同源性和保守结构折叠的评估，我们强调了设计更特异和有效的选择性靶向JAK家族成员的抑制剂的有趣前景。我们的比较研究提供了一个平台，合理设计的精确和有效的抑制剂，选择性靶向JAK家族成员。
Janus kinases (JAKs) belong to a crucial family of tyrosine kinases, implicated in the patho-physiology of multiple cancer types, and serve as striking therapeutic targets. To date, many potent, either ATP-competitive (PTK domain) or non-ATP-competitive JAK inhibitors have been identified. Among them, Tyrphostin AG-490 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide) is a well-known ATP-competitive inhibitor. However, its mode of action, details of interacting residues, and induced conformational changes in JAK-specific binding sites remain elusive. Here, through comparative structure analysis, molecular docking, and molecular dynamics simulation assays, we explored comparative binding patterns of AG-490 against JAK1, JAK2, and JAK3. Our results entail noteworthy observations about the binding affinity of AG-490 by illustrating distinctive amino acid residues lying at the conserved ATP-binding domains of JAK family members. By subsequent assessment of their structural homology and conserved structural folds, we highlight intriguing prospects to design more specific and potent inhibitors for selective targeting of JAK family members. Our comparative study provides a platform for the rational design of precise and potent inhibitor for selective targeting of JAK family members.